There is a large need for skeletal muscle tissue in craniofacial reconstructive surgery. The long-term goal of the applicants' research is to engineer fully functional skeletal muscle by combining cultured myoblasts with biodegradable polymer matrices. The polymer matrices will serve as a template for new tissue formation, and guide the differentiation of myoblasts in contact with the matrix into functional muscle tissue mass. Degradation of the polymer matrices would ultimately lead to a completely natural new skeletal muscle tissue. The hypothesis guiding the current proposal is that the growth and differentiation of skeletal myoblasts on three-dimensional biodegradable matrices can be controlled by the application of defined mechanical and electrical stimuli to cells attached to the matrix via specific adhesion ligands. To address this hypothesis we propose to synthesize polymer matrices from alginate in which specific myoblast adhesion peptides have been coupled. The role of the peptide type and density in controlling myoblast proliferation and differentiation will first be determined in static culture conditions. Subsequently, defined regimens of mechanical strain and electrical stimulation will be applied separately and in concert to myoblasts adherent to polymer fibers via specific adhesion ligands. These stimuli are intended to mimic those applied during normal muscle development. Biodegradable polymers based on alginate will also be synthesized, and utilized to determine the optimal relation between tissue development time and polymer degradation rate which yields functional, completely natural skeletal muscle tissue. The successful completion of these aims will lead to the synthesis and validation of biodegradable matrices which can be used to engineer skeletal muscle. The production of skeletal muscle constructs with normal contractile function is an important step toward the tissue engineering of whole skeletal muscles in vitro. These studies will also greatly improve the current understanding of the roles of both adhesion ligands and physical stimuli in the regulation of myoblast differentiation and muscle function. This proposal represents, to our knowledge, the first effort to determine if these two regulatory pathways interact, and the first attempt to exploit these factors in the engineering of three-dimensional skeletal muscle tissue. If these regulatory pathways are found to interact it will significantly alter the current understanding of mechanotransduction in skeletal muscle.
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